Related Experiment Video
Updated: Jun 13, 2026
Modeling Tuberculosis in Mycobacterium marinum Infected Adult Zebrafish
Published on: October 8, 2018
Modulation of Ferroptosis During Early Mycobacterium tuberculosis Infection Contributes to Beijing Lineage Strain
Joshua J Ivie1, Sylvia Stull1, Ethan Bustad1
1Center for Global Infectious Disease Research, Seattle Children's Research Institute.
Abstract:
Although spread of internalized Mtb from the initial infected alveolar macrophages (AMs) is a crucial determinant of infection outcomes, the role of cell death in facilitating this spread, and how it is regulated by Mtb remains poorly understood. Ferroptosis, a lipid peroxidation-mediated form of necrotic cell death, contributes to pathology during later stages of infection. However, the role of ferroptosis in early AM cell death remains inadequately defined, and its induction during infection has been primarily studied with the laboratory strain, H37Rv. Using gene set variation analysis of single cell RNAseq data profiling Mtb-infected murine lungs, we found that the hypervirulent Beijing sublineage clinical strain SA161 is associated with an elevated pro-ferroptotic transcriptional response in AMs compared to H37Rv by 17 days post infection. Consistent with these transcriptional profiles, we found that SA161 induced increased lipid peroxidation in comparison to H37Rv during infection in vitro and in vivo. Administration of the lipid peroxidation inhibitor, ferrostatin-1 (Fer-1), reduces this Mtb-induced lipid peroxidation. Notably, we found that administration of Fer-1 to Mtb-infected mice significantly reduced bacterial burden for SA161 at 14 dpi while having no effect on H37Rv. Microscopic analysis of SA161-infected lung lesions at 14 dpi suggests that inhibition of ferroptosis-driving lipid peroxidation results in a greater proportion of AMs amongst infected cells and decreased neutrophil-associated IFN signaling. Collectively, these findings reveal that ferroptosis plays an important role during early infection with virulent clinical strains of Mtb by influencing bacterial spread and signaling of immune cell responders, potentially informing host-directed intervention strategies.
Insights
A virulent clinical strain of Mycobacterium tuberculosis (Mtb) induces ferroptosis, a cell death pathway, in alveolar macrophages (AMs), promoting bacterial spread. Inhibiting this ferroptosis reduces bacterial burden and alters immune signaling during early infection.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Spread of Mycobacterium tuberculosis (Mtb) from infected alveolar macrophages (AMs) is critical for infection outcomes.
- The role of cell death, particularly ferroptosis, in early Mtb infection and its regulation by Mtb strains are poorly understood.
- Ferroptosis, a lipid peroxidation-mediated cell death, is implicated in later stages of Mtb infection, but its early role in AMs is undefined.
Purpose of the Study:
- To investigate the role of ferroptosis in early AM cell death during Mtb infection.
- To compare the ferroptotic response induced by a hypervirulent clinical Mtb strain (SA161) versus a laboratory strain (H37Rv).
- To assess the impact of inhibiting ferroptosis on bacterial burden and immune responses in Mtb-infected mice.
Main Methods:
- Gene set variation analysis of single-cell RNAseq data from Mtb-infected murine lungs.
- In vitro and in vivo assessment of lipid peroxidation induced by Mtb strains.
- Administration of ferrostatin-1 (Fer-1), a lipid peroxidation inhibitor, to Mtb-infected mice.
- Microscopic analysis of lung lesions to evaluate cell populations and immune signaling.
Main Results:
- The hypervirulent Mtb strain SA161 induced a stronger pro-ferroptotic transcriptional response in AMs compared to H37Rv.
- SA161 caused increased lipid peroxidation in AMs both in vitro and in vivo, which was reduced by Fer-1.
- Fer-1 administration significantly reduced bacterial burden for SA161 infection at 14 days post-infection but had no effect on H37Rv.
- Inhibition of ferroptosis in SA161-infected lungs led to a higher proportion of AMs and decreased neutrophil-associated IFN signaling.
Conclusions:
- Ferroptosis plays a significant role in early infection with virulent clinical Mtb strains.
- Ferroptosis influences bacterial spread and the signaling of immune responders like neutrophils.
- Targeting ferroptosis-driven lipid peroxidation may offer a host-directed strategy for treating Mtb infections caused by virulent strains.
Related Concept Videos
01:28Regulation of Bacterial Virulence
01:29Pulmonary Tuberculosis I
Causative Organism
The primary infectious agent causing tuberculosis is Mycobacterium tuberculosis, a slow-growing, acid-fast, aerobic rod that exhibits sensitivity to heat and ultraviolet light. Instances of Mycobacterium bovis and Mycobacterium avium contributing to the development of TB infection are rare.
Mode of...
01:20Determinants of Bacterial Pathogenicity and Virulence
01:26Bacterial Meningitis II: Pathophysiology